Project Summary Remarkable developments in ophthalmic imaging technologies, including optical coherence tomography (OCT) and more recently adaptive-optics retinal imaging have enabled micron-level resolution and transformed diagnosis and management of ophthalmic diseases. Unfortunately, still many of the retinal structures cannot be resolved in vivo, let alone sub-cellular structures. A key shortcoming shared by existing optical approaches for retinal imaging is that the attainable size of the eye?s pupil sets a limit on the numerical aperture, and hence the lateral resolution. At the same time, in many cases, illumination and detection pathways have to be separated within this sole aperture of the eye, further constraining the achievable resolution. In addition, contrast variations among the structures of interest, noise of the overall system, and eye motion artifacts further limit current approaches. Time is ripe for another ophthalmic imaging revolution that overcomes existing constraints and enables the uncovering of retinal structures at the cellular and sub-cellular level in the living eye. The objective of this project is to address this unmet need by exploring speckle structured-illumination of the ocular fundus. Furthermore, the project will investigate laser Illumination through the sclera to overcome the numerical- aperture limitations inherent to pupil-based illumination. The proposed approach allows the formation of speckle patterns on the ocular fundus that are randomly shifted (scanned) by the naturally occurring involuntary fixational movements of the eye. The backscattered light is collected through the pupil and post-processed to recover super-resolved retinal images, beyond the capabilities of state-of-the art imaging modalities. Interestingly, the eye point spread function is obtained as a by-product describing the aberrations of eye. Movement artifacts are avoided by collecting short exposure image frames which are carefully registered before reconstruction. An eye movement sensing subsystem enables sub-diffraction precision registration. The investigators have assembled the required multifaceted expertise to explore, for the first time, these bold ideas. It includes leaders in random media, super-resolution, and ophthalmic instrument development. At the end of this project, we expect to be in a unique position to transfer the technique into practice through the team?s existing wide cooperative network of ophthalmology departments. Armed with the unprecedented spatial resolution of the proposed technique, these future interdisciplinary investigations can drive new insights into retinal disease mechanisms and enable earlier diagnosis of retinal diseases, including some of the most severe vision disabling conditions (e.g., retinal dystrophies, age-related macular degeneration, glaucoma), while driving innovative therapies to protect cells before irreversible cell death and blindness occurs.